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The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis


Renkema, K Y; Velic, A; Dijkman, H B; Verkaart, S; van der Kemp, A W; Nowik, M; Timmermans, K; Doucet, A; Wagner, C A; Bindels, R J; Hoenderop, J G (2009). The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. Journal of the American Society of Nephrology (JASN), 20(8):1705-1713.

Abstract

Hypercalciuria increases the risk for urolithiasis, but renal adaptive mechanisms reduce this risk. For example, transient receptor potential vanilloid 5 knockout (TPRV5(-/-)) mice lack kidney stones despite urinary calcium (Ca(2+)) wasting and hyperphosphaturia, perhaps as a result of their significant polyuria and urinary acidification. Here, we investigated the mechanisms linking hypercalciuria with these adaptive mechanisms. Exposure of dissected mouse outer medullary collecting ducts to high (5.0 mM) extracellular Ca(2+) stimulated H(+)-ATPase activity. In TRPV5(-/-) mice, activation of the renal Ca(2+)-sensing receptor promoted H(+)-ATPase-mediated H(+) excretion and downregulation of aquaporin 2, leading to urinary acidification and polyuria, respectively. Gene ablation of the collecting duct-specific B1 subunit of H(+)-ATPase in TRPV5(-/-) mice abolished the enhanced urinary acidification, which resulted in severe tubular precipitations of Ca(2+)-phosphate in the renal medulla. In conclusion, activation of Ca(2+)-sensing receptor by increased luminal Ca(2+) leads to urinary acidification and polyuria. These beneficial adaptations facilitate the excretion of large amounts of soluble Ca(2+), which is crucial to prevent the formation of kidney stones.

Hypercalciuria increases the risk for urolithiasis, but renal adaptive mechanisms reduce this risk. For example, transient receptor potential vanilloid 5 knockout (TPRV5(-/-)) mice lack kidney stones despite urinary calcium (Ca(2+)) wasting and hyperphosphaturia, perhaps as a result of their significant polyuria and urinary acidification. Here, we investigated the mechanisms linking hypercalciuria with these adaptive mechanisms. Exposure of dissected mouse outer medullary collecting ducts to high (5.0 mM) extracellular Ca(2+) stimulated H(+)-ATPase activity. In TRPV5(-/-) mice, activation of the renal Ca(2+)-sensing receptor promoted H(+)-ATPase-mediated H(+) excretion and downregulation of aquaporin 2, leading to urinary acidification and polyuria, respectively. Gene ablation of the collecting duct-specific B1 subunit of H(+)-ATPase in TRPV5(-/-) mice abolished the enhanced urinary acidification, which resulted in severe tubular precipitations of Ca(2+)-phosphate in the renal medulla. In conclusion, activation of Ca(2+)-sensing receptor by increased luminal Ca(2+) leads to urinary acidification and polyuria. These beneficial adaptations facilitate the excretion of large amounts of soluble Ca(2+), which is crucial to prevent the formation of kidney stones.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2009
Deposited On:18 Aug 2009 11:26
Last Modified:05 Apr 2016 13:19
Publisher:American Society of Nephrology
ISSN:1046-6673
Publisher DOI:https://doi.org/10.1681/ASN.2008111195
Official URL:http://jasn.asnjournals.org/cgi/reprint/20/8/1705
PubMed ID:19470676
Permanent URL: https://doi.org/10.5167/uzh-20256

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